Characterization of a new cytotoxin that contributes to Staphylococcus aureus pathogenesis

By Ashley L. DuMont, Tyler K. Nygaard, Robert L. Watkins, Amanda J. Smith, L. Kozhaya, B. N. Kreiswirth, Bo Shopsin, D. Unutmaz, Jovanka M. Voyich, Victor J. Torres. 2010

205 citations recorded by the source corpus.

Staphylococcus aureus is an important pathogen that continues to be a significant global health threat because of the prevalence of methicillin‐resistant S. aureus strains (MRSA). The pathogenesis of this organism is partly attributed to the production of a large repertoire of cytotoxins that target and kill innate immune cells, which provide the first line of defence against S. aureus infection. Here we demonstrate that leukocidin A/B (LukAB) is required and sufficient for the ability of S. aureus, including MRSA, to kill human neutrophils, macrophages and dendritic cells. LukAB targets the plasma membrane of host cells resulting in cellular swelling and subsequent cell death. We found that S. aureus lacking lukAB are severely impaired in their ability to kill phagocytes during bacteria–phagocyte interaction, which in turn renders the lukAB‐negative staphylococci more susceptible to killing by neutrophils. Notably, we show that lukAB is expressed in vivo within abscesses in a murine infection model and that it contributes significantly to pathogenesis of MRSA in an animal host. Collectively, these results extend our understanding of how S. aureus avoids phagocyte‐mediated clearance, and underscore LukAB as an important factor that contributes to staphylococcal pathogenesis.

Subfields: Immunology, Infectious Diseases, Microbiology

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Citations in the corpus

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus (2014, methodology): “Around the same time, an additional study by DuMont et al. used isogenic leucocidin deletion mutants in S. aureus strain Newman as well as proteomic studies of S. aureus culture filtrates to identify a novel leucocidin responsible for lytic activity of S. aureus culture supernatants derived from bac”
Exploiting dominant‐negative toxins to combat Staphylococcus aureus pathogenesis (2016, unknown): “We had to use a leukocidin minus strain since LukAB is highly potent during ex vivo infection of PMNs, masking any contribution of the other toxins [41].”
Identification of biologic agents to neutralize the bicomponent leukocidins of Staphylococcus aureus (2019, result): “Consistent with previously published data (42, 43), S.”
Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection. (2013, methodology): “…of toxins capable of killing PMNs (Alonzo and Torres, 2013) and LukED is produced at sublytic quantities by S. aureus in broth culture (Alonzo et al., 2012; DuMont et al., 2011), we opted to use an engineered S. aureus strain lacking all the pore-forming toxins (hla, lukAB, hlgACB, and lukED).”
Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils (2013, methodology): “5% agar at 37°C or in Roswell Park Memorial Institute medium (RPMI 1640; Invitrogen) supplemented with 1% Casamino Acids (RPMI CAS) (26, 31), with shaking at 180 rpm, unless otherwise indicated.”
Disarming Staphylococcus aureus from destroying human cells by simultaneously neutralizing six cytotoxins with two human monoclonal antibodies (2017, background): “aureus.(42,51,52) We found that ASN-1 or ASN-2 alone had variable”
Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular (2015, methodology): “aureus toxin [20,21], is a predominant cytolytic leukotoxin responsible for inducing programmed inflammatory cell death in human monocytes.”
Staphylococcus aureus Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin (2019, methodology): “Previously, it was shown that human PMNs induce the expression and production of LukAB (11, 21, 22), which is associated with the dominant role of this toxin in infections using primary human PMNs (11, 20, 23).”
Evolution of hypervirulence by a MRSA clone through acquisition of a transposable element (2014, methodology): “Briefly, 2 × 105 PMNs per well were plated in 96-well tissue culture treated plates in a final volume of 100 μl RPMI (Gibco) supplemented with 10% heat-inactivated fetal bovine serum.”